RUNX1/CEBPA Mutation in Acute Myeloid Leukemia Promotes Hypermethylation and Indicates for Demethylation Therapy.
Fiche publication
Date publication
septembre 2022
Journal
International journal of molecular sciences
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DEMIDOV Oleg
Tous les auteurs :
Romanova EI, Zubritskiy AV, Lioznova AV, Ogunleye AJ, Golotin VA, Guts AA, Lennartsson A, Demidov ON, Medvedeva YA
Lien Pubmed
Résumé
Acute myeloid leukemia (AML) is a rapidly progressing heterogeneous disease with a high mortality rate, which is characterized by hyperproliferation of atypical immature myeloid cells. The number of AML patients is expected to increase in the near future, due to the old-age-associated nature of AML and increased longevity in the human population. RUNX1 and CEBPA, key transcription factors (TFs) of hematopoiesis, are frequently and independently mutated in AML. RUNX1 and CEBPA can bind TET2 demethylase and attract it to their binding sites (TFBS) in cell lines, leading to DNA demethylation of the regions nearby. Since TET2 does not have a DNA-binding domain, TFs are crucial for its guidance to target genomic locations. In this paper, we show that RUNX1 and CEBPA mutations in AML patients affect the methylation of important regulatory sites that resulted in the silencing of several RUNX1 and CEBPA target genes, most likely in a TET2-dependent manner. We demonstrated that hypermethylation of TFBS in AML cells with RUNX1 mutations was associated with resistance to anticancer chemotherapy. Demethylation therapy restored expression of the RUNX1 target gene, BIK, and increased sensitivity of AML cells to chemotherapy. If our results are confirmed, mutations in RUNX1 could be an indication for prescribing the combination of cytotoxic and demethylation therapies.
Mots clés
AML, BIK, CEBPA, DNA methylation, RUNX1, TET2, epigenetics
Référence
Int J Mol Sci. 2022 09 27;23(19):